The Role of Glycoconjugates in Mediating Human Fertilization and Induction of Fetomaternal Tolerance
Using the hemizona assay (HZA), a in vitro sperm-egg binding assay, we show that specific glycoconjugates known to inhibit immune cell interactions mediated by the selectins, potently block human sperm-egg binding. The selectin ligand sialyl Lewisx inhibits sperm binding in the HZA by 60% at a concentration of 1 mg/ml. Our data indicates that glycodelin-A, a endometrial glycoprotein known to block sperm-egg binding in the HZA at low concentrations expresses unusual fucosylated lacdiNAc type glycans. The fucosylated lacdiNAc type sugars have been previously shown to be 15-20 fold more potent ligands of E-selectin. Glycodelin-S a seminal plasma glycoform of glycodelin-A does not express such unusual glycans and is not contraceptive. These results support our hypothesis that human sperm-egg binding may involve a selectin-like event. Periodate oxidation under conditions that affect only the terminal sugar residues results in a 30-40% loss in sperm binding. Treatment of the ZP with neuraminidase and endo-β-galactosidase results in a 2.5 and 4 fold enhancement in sperm binding respectively. However, sequential treatment of the ZP with neuraminidase and periodate results in 80% decrease in sperm binding. These studies strongly indicate that ZP glycans are essential for mediating human gamete binding. Furthermore, efficient initial human sperm egg binding in vivo may require a prior activation event involving desialylation of the gametes. In this study we provide preliminary evidence that human gametes express the bisecting type glycans. Our studies indicate that these glycans potently inhibit natural killer (NK) cells, the predominant cell type expressed in the uterus during pregnancy. Other glycoconjugates like $\alpha$-fetoprotein, expressed in the uterus during pregnancy, also carry the bisecting-type glycans. Based on these observations we propose that glycoconjugates expressed during pregnancy protect are responsible for mediating feto-maternal tolerance. We refer to this model for as the Human Feto-Embryonic Defense System hypothesis. Finally our data suggests that parasites like schistosomes, filarial worms, and the human immunodeficiency virus may be evading the host's immune responses by a similar by expressing immunosuppressive glycoconjugates on their coats.
Glycoconjugates, Human fertilization, Fetomaternal tolerance, Anatomy, Cell Biology, Obstetrics and Gynecology, Physiology
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